Methods and compositions for inhibiting the growth of aberrant cells are desirable in a variety of situations, for example, to suppress the growth of pathogenic microorganisms infecting a host subject or to suppress the growth of cancer cells in a host subject. Various types of agents for inhibiting aberrant cell growth have been developed. For example, to inhibit the growth of bacterial cells, natural antibiotics (chemical substances produced by microorganisms such as bacteria, fungi and actinomycetes) have been identified and characterized. Synthetic antibiotics, such as sulfonamides and quinolones, have also been developed. Growth of mammalian cells (e.g., malignant cells) can be inhibited by a variety of toxic compounds or therapies, such as nucleoside analogs, metal-containing drugs or radiation treatment, which interfere with normal cellular metabolism.
Transformation, or malignant transformation, of cells results in changes in their growth characteristics and can cause them to form tumors in the infected animals. For example, aberrant cells can be associated with changes in growth control, cell morphology, membrane characteristics, protein secretion and gene expression. Although aberrant cell transformation can occur spontaneously, it can be caused by a chemical or irradiation or may result from infection by a tumor virus. Little is known about the underlying molecular events.
DNA ligase is an enzyme which is involved in DNA replication, repair and recombination. DNA ligase acts by joining single and doubled stranded DNA with the formation of phosphodiesters bonds. For example, eurkaryotic DNA ligases react with ATP, thereby forming covalent enzyme-AMP intermediates. The enzymes then transfer the AMP group to the 5' end of the DNA to complete the joining reaction. DNA ligase joining activity has been implicated in the proliferation of aberrant cell growth, such as in bacteria and in mammalian cancer.
Although known growth inhibitory agents have been used successfully to suppress the growth of cells to ameliorate certain disease states, there are limitations to their use. For example, the widespread use of antibiotics has increasingly led to the problem of resistant pathogens whose growth can no longer be inhibited by known antibiotics. The appearance of multi-drug resistant pathogens has prompted a search for new classes of antibiotics which are structurally and/or functionally different from existing drugs. Drugs having new mechanisms of action could be effective against resistant microorganisms, where conventional drugs can no longer be used. Chemotherapeutic agents for suppressing the growth of mammalian cells (e.g., malignant cells) also have limitations. Chemotherapeutic agents often have deleterious side effects and/or show only limited efficacy.